Journal article
3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes
Aging cell, Vol.24(7), e70054
07/2025
DOI: 10.1111/acel.70054
PMCID: PMC12266761
PMID: 40285369
Abstract
Age-related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three-dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block-face scanning electron microscopy (SBF-SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age-related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age-related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog in Drosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age-related structural changes in mitochondria and further suggest that exercise may mitigate age-related structural decline through modulation of mitofusin 2.
Details
- Title: Subtitle
- 3D Mitochondrial Structure in Aging Human Skeletal Muscle: Insights Into MFN-2-Mediated Changes
- Creators
- Estevão Scudese - Pontifícia Universidade Católica de São PauloAndrea G Marshall - Vanderbilt UniversityZer Vue - Vanderbilt UniversityVernat Exil - Department of Pediatrics, Div. of Cardiology, St. Louis University School of Medicine, St. Louis, MO, USABenjamin I Rodriguez - Vanderbilt UniversityMert Demirci - Vanderbilt University Medical CenterLarry Vang - Vanderbilt UniversityEdgar Garza Lopez - University of IowaKit Neikirk - Vanderbilt UniversityBryanna Shao - Vanderbilt UniversityHan Le - Vanderbilt UniversityDominique Stephens - Vanderbilt UniversityDuane D Hall - University of IowaRahmati Rostami - Cornell UniversityTaylor Rodman - Vanderbilt UniversityKinuthia Kabugi - Vanderbilt UniversityJian-Qiang Shao - Central Microscopy Research Facility, Iowa City, IA, USAMargaret Mungai - Vanderbilt UniversitySalma T AshShareef - University of IowaInnes Hicsasmaz - University of Iowa, Internal MedicineSasha Manus - Vanderbilt UniversityCelestine N Wanjalla - Vanderbilt University Medical CenterAaron Whiteside - Wright State UniversityRevathi Dasari - Department of Biology, Indian Institute of Science Education and Research (IISER), Tirupati, AP, IndiaClintoria R Williams - Wright State UniversitySteven M Damo - Fisk UniversityJennifer A Gaddy - Tennessee Valley Healthcare Systems, U.S. Department of Veterans Affairs, Nashville, TN, USABrian Glancy - NIAMS, NIH, Bethesda, MD, USAEstélio Henrique Martin Dantas - PSA (United States)André Kinder - FMP (Czechia)Ashlesha Kadam - Wake Forest UniversityDhanendra Tomar - Wake Forest UniversityFabiana Scartoni - Laboratory of Biosciences of Human Motricity (LABIMH) of the Federal University of State of Rio de Janeiro (UNIRIO), Rio de Janeiro, BrazilMatheus Baffi - Pontifícia Universidade Católica de São PauloMelanie R McReynolds - Pennsylvania State UniversityMark A Phillips - Oregon State UniversityAnthonya Cooper - University of PittsburghSandra A Murray - University of PittsburghAnita M Quintana - The University of Texas at El PasoNelson Wandira - Busoga UniversityOkwute M Ochayi - Baze UniversityMagdalene Ameka - University of NairobiAnnet Kirabo - Vanderbilt UniversitySepiso K Masenga - Mulungushi UniversityChanel Harris - Meharry Medical CollegeAshton Oliver - Meharry Medical CollegePamela Martin - Meharry Medical CollegeAmadou Gaye - Meharry Medical CollegeOlga Korolkova - Meharry Medical CollegeVineeta Sharma - Meharry Medical CollegeBret C Mobley - Vanderbilt University Medical CenterPrasanna Katti - National Heart Lung and Blood InstituteAntentor Hinton - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Aging cell, Vol.24(7), e70054
- DOI
- 10.1111/acel.70054
- PMID
- 40285369
- PMCID
- PMC12266761
- NLM abbreviation
- Aging Cell
- ISSN
- 1474-9726
- eISSN
- 1474-9726
- Publisher
- WILEY
- Grant note
- UL1 RR024975-01 / NCRR NIH HHS 5P30CA068485-29 / Vanderbilt Cell Imaging Shared Resource 5I01BX005352-04 / Department of Veterans Affairs Office of Research Award S10RR025497 / NIH HHS ANRF/ECRG/2024/001042/LS / ANRF CA163069 / NIH HHS EES2112556 / NSF 1021868.01 / Burroughs Wellcome Fund American Society of Nephrology KidneyCure Transition to Independence Grant, ASN Foundation 24IVPHA1297559 / American Heart Association
- Language
- English
- Electronic publication date
- 04/25/2025
- Date published
- 07/2025
- Academic Unit
- Stead Family Department of Pediatrics; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984815910102771
Metrics
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